Figures

Abstract

Introduction

It has been suggested that vitamin D is effective to prevent mortality. However, there is no consistent conclusion that the effects of vitamin D supplementation on all-cause mortality are associated with duration of treatment. We conducted a meta-analysis regarding this issue in an effort to provide a more robust answer.

Methods

A comprehensive search in a number of databases, including MEDLINE, Embase and The Cochrane Central Register of Controlled Trials, was conducted for collecting randomized controlled trials (RCTs) on vitamin D supplementation preventing mortality. Two investigators independently screened the literature according to the inclusive and exclusive criteria and the relative data were extracted. Data analysis was performed by using Review Manager 5.0 software.

Results

Data from forty-two RCT s were included. Vitamin D therapy significantly decreased all-cause mortality with a duration of follow-up longer than 3 years with a RR (95% CI) of 0.94 (0.90–0.98). No benefit was seen in a shorter follow-up periods with a RR (95% CI) of 1.04 (0.97–1.12). Results remain robust after sensitivity analysis. The following subgroups of long-term follow-up had significantly fewer deaths: female only, participants with a mean age younger than 80, daily dose of 800 IU or less, participants with vitamin D insufficiency (baseline 25-hydroxyvitamin D level less than 50 nmol/L) and cholecalciferol therapy. In addition, the combination of vitamin D and calcium significantly reduced mortality and vitamin D alone also had a trend to decrease mortality in a longer time follow up.

Conclusions

The data suggest that supplementation of vitamin D is effective in preventing overall mortality in a long-term treatment, whereas it is not significantly effective in a treatment duration shorter than 3 years. Future studies are needed to identify the efficacy of vitamin D on specific mortality, such as cancer and cardiovascular disease mortality in a long-term treatment duration.

Funding: This study was funded by the grants from National Natural Science Foundation of China (81102450). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Vitamin D plays a key role in human health, while the prevalence of vitamin D insufficiency is high, especially among the elderly [1]. It has recently been identified to be associated with skeletal diseases such as osteoporosis [2] and non-skeletal diseases including cancer [3-5], cardiovascular disease [6], and kidney disease [7,8]. Meta-analysis has suggested that low vitamin D baseline levels are associated with increased risks of mortality [9]. This issue is becoming to be paramount importance given the high prevalence of vitamin D deficiency worldwide [10].

It has been documented that vitamin D supplementation prevents fractures and falls [11,12]. In recent years, several studies on meta-analysis of randomized controlled trials with regard to supplementation of vitamin D on total mortality have been published, which found that vitamin D supplementation reduced total mortality when given together with calcium, but not with vitamin D alone [13-16], and. A Cochrane systematic review found that vitamin D significantly decreased mortality in those with vitamin D insufficiency [15]. However, long-term health effects of vitamin D supplementation still remains unclear.

To investigate whether the effects of vitamin D supplementation on all-cause mortality are associated with duration of treatment, we undertook a comprehensive systematic database search and meta-analysis to access the effects of vitamin D supplementation on all-cause mortality.

Materials and Methods

Search strategy

A literature search was conducted on a number of databases, including Medline, Embase and The Cochrane Central Register of Controlled Trials for the period January 1960 to January 2013, to identify RCTs. Our core search terms were “randomized controlled trial”, “vitamin D”, “vitamin D2”, “vitamin D3”, “ergocalciferol”, “cholecalciferol”, “mortality”, “death”. We also searched for any additional studies in the reference lists of recent meta-analysis of vitamin D treatment for mortality. Our searches were limited to human trials, and no language or time restriction was applied.

Eligibility criteria

The preliminary search results were then examed on the basis of the following criteria.

Types of studies.

Randomized controlled trials evaluating an intervention with vitamin D were identified as part of the review, while review articles, commentaries, letters, observational studies were excluded.

Interventions.

The intervention group was restricted to vitamin D alone or in combination with calcium treatment; the control group was placebo, no treatment or calcium only therapy. Studies of patients receiving active vitamin D and intramuscular injection of vitamin D were excluded from the review.

Outcome.

The number of deaths was reported separately for the vitamin D treatment group and the control group. For articles with a large sample size, if the number of deaths was not reported by treatment, we tried to contact the authors to obtain the missing data.

Data Extraction and Quality Assessment

Two statisticians independently extracted information from included trials using a standardized form., and then another statisticians verified them. The following information was subtracted from the study: first author, publishing year, sample size, duration, dwelling, intervention, serum 25 (OH) D levels at baseline, and main results (the number of participants who died). Quality assessment of included trials was conducted using the Cochrane Collaboration’s tool [17]. Methodological features most relevant to the control of bias were examined, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias [17]. Quality assessment was performed by two independent researchers.

Data Synthesis and Analysis

Meta-analysis were undertaken using Review Manager (Version 5.0). The primary outcome was the number of participants who died during follow-up. The pre-planned analysis was vitamin D arm (with or without calcium) versus control arm (placebo, calcium, or no treatment) according to duration of treatment. Mantel-Haenszel method was used to calculate risk ratios (RRs) and their 95% confidence intervals (CI). The I2 statistic was used to assess the presence of heterogeneity, which ranges from 0% to 100% [18]. In case of lack of heterogeneity (I2 < 50%), fixed-effects model was used to assess the overall estimate, or else random-effects model was chosen. The Begg test [19] and Egger test [20] were used to evaluate the presence of publication bias regarding our primary end points (RR of mortality). A 2-tailed P value of less than .05 was considered as statistically significant.

Sensitivity analysis and subgroup analysis

A sensitivity analysis was conducted by excluding studies with high risk of bias. Subgroup analysis was conducted only on trials with the duration of treatment at least 3 years or longer. The effect of vitamin D was assessed according to gender (male or female), age group (< 80 years or ≥ 80 years), dose of oral vitamin D daily (≤800 IU or >800 IU), baseline level of 25- hydroxyvitamin D (< 50 nmol per liter or ≥ 50 nmol per liter), type of vitamin D (ergocalciferol or cholecalciferol) and calcium co-administration status (Vitamin D + calcium vs. Calcium, Vitamin D + calcium vs. Placebo, or Vitamin D vs. Placebo), and specific mortality (cancer mortality, cardiovascular mortality)

Results

Search Results

A total of 4,024 unique titles and abstracts were found from initial searches of the electronic database. With the inclusion/exclusion criteria, 3,861 of which were excluded by scrutinizing the titles and abstracts, and 121 articles were further excluded after full text review. A total of 42 RCTs that met inclusion criteria were included in the final analysis [21-62]. The details of study selection flow were explicitly described in Figure 1.

Study Characteristics

The main characteristics of the included studies are shown in Table 1 (1). Publishing year: The RCTs were published from 1992 to 2012 (2). Treatment duration: 29 RCTs have treatment durations less than 3 years, and the remaining 13 RCTs have treatment durations of 3 years or longer (3). Number of patients: A total of 85,466 patients (42,561 in the vitamin D group and 42,905 in the control group) were included in these 42 RCTs (4). Age of patients: The number of participants in each trial ranged from 46 to 36,282 and mean age of participants ranged from 37 to 89 years, with most participants older than 60 years (5). Vitamin D type and dose: Vitamin D2 was used in 10 studies and vitamin D3 was used in the remaining 32 studies. Vitamin D2 or D3 was given as daily doses ranging from 300 to 3,333 IU. Calcium supplementation was used in 26 trials (6). Baseline vitamin D status: 37 trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 15 trials had baseline 25-hydroxyvitamin D levels at or above cutoff for vitamin D adequacy (50 nmol/l or 20 ng/ml). Participants in the remaining 22 trials had baseline 25-hydroxyvitamin D levels in a range of vitamin D insufficiency (< 50 nmol/l or 20 ng/ml). The other 5 trials did not report the baseline vitamin D status of participants (7). Bias risk: 26 studies had a low risk of bias, and 16 had a high risk of bias (Table 2).

Participants had had an osteoporotic fracture within the last 10 years

Vit D3 800 IU daily + Ca1000 daily

99

77

NA

1 year

No treatment

35

75.6

NA

Harwood 2004

Elderly women after hip fracture

Vit D3 800 IU+ Ca 1000 mg daily

29

83

29

1 year

No treatment

35

81

30

Meier 2004

Healthy adults

VitD3 500 IU+ Ca 500 mg daily

30

55.2

75.25

1.5 years

No treatment

25

57.9

77

Cooper 2003

Women who were ≥ 1 y postmenopausal

Vit D2 100000 IU weekly + Ca 1000 daily

93

56.5

81.6

2 years

Ca 1000 daily

94

56.1

82.6

Latham 2003

Recruited from geriatric rehabilitation center

Vit D2 300,000 IU/im/once

108

80

38

6 months

Placebo

114

79

48

Meyer 2002

Nursing home residents

Vit D3 400 IU daily

569

84

47

2 years

Placebo

575

85

51

Chapuy 2002

Elderly ambulatory institutionalized women

Vit D3 800 IU daily + Ca 1200 mg daily

393

85

22.5

2 years

Placebo

190

85

22.7

Krieg 1999

Elderly women living in nursing homes

Vit D3 880 IU daily + Ca 1000 mg daily

124

84

29.8

2 years

No treatment

124

85

29.3

Bæksgaard 1998

Healthy postmenopausal women

Vit D3 560 IU daily + Ca 1000 mg daily

80

62.9

NA

2 years

No treatment

80

61.8

NA

Ooms 1995

Elderly women

VitD3 400 IU daily

177

80.1

27

2 years

Placebo

171

80.6

25

Chapuy 1992

Elderly living in apartments or nursing homes

Vit D3 800 IU daily + Ca 1200 mg daily

1634

84

40

2 years

Placebo

1636

84

32.5

Table 1. Characteristics of the included studies.

Vit D, vitamin D; Ca, calcium

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Study

Random sequence Generation (selection bias)

Allocation Concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting Reporting (reporting bias)

Other bias

Trials have a follow-up of 3 years or longer

Avenell 2012

L

L

L

L

L

L

L

Bolland 2011

L

L

L

L

L

L

L

Sanders 2010

L

L

L

L

L

L

L

Salovaara 2010

L

L

H

H

L

L

L

Zhu 2008

L

L

L

L

L

L

L

Lappe 2007

L

L

L

L

H

L

L

Lyons 2007

L

L

L

L

L

L

L

Aloia 2005

L

L

L

L

L

L

L

Larsen 2004

U

H

H

H

H

U

H

Trivedi 2003

L

L

L

L

L

L

L

Komulainen 1999

L

L

L

L

L

L

L

D-Hughes 1997

L

L

L

L

L

L

L

Lips 1996

L

L

L

L

L

L

L

Trials have a follow-up of less than 3 years

Alvarez 2012

L

L

L

L

L

L

L

Lehouck 2012

L

L

L

L

L

L

L

TiIDE trial 2012

L

U

U

U

L

L

H

Wasse 2012

L

L

L

L

L

L

L

Witham 2010

L

L

L

L

L

L

L

Lips 2010

L

L

L

L

L

L

L

Wejse 2009

L

L

L

L

L

L

L

Chel 2008

U

U

U

U

L

L

L

Bjorkman 2008

L

L

L

L

L

L

L

Prince 2008

L

L

L

L

L

L

L

Burleigh 2007

L

L

L

L

L

L

L

Boton-Smith 2007

L

L

L

L

L

L

L

Broe 2007

L

L

L

L

L

L

L

Law 2006

L

H

H

H

L

L

U

Schleithoff 2006

L

L

L

L

L

L

L

Brazier 2005

L

U

U

U

L

L

H

Flicker 2005

L

L

L

L

L

L

L

Porthouse 2005

L

L

H

H

L

U

H

Avenell 2004

L

H

H

H

L

L

H

Harwood 2004

L

L

H

H

L

L

H

Meier 2004

U

U

H

H

L

L

U

Cooper 2003

L

L

L

L

L

L

L

Latham 2003

L

L

L

L

L

L

L

Meyer 2002

H

H

L

L

L

L

H

Chapuy 2002

U

U

U

U

L

L

H

Krieg 1999

U

H

H

H

L

L

L

Bæksgaard 1998

U

U

L

L

L

H

L

Ooms 1995

L

L

L

L

L

L

L

Chapuy 1992

U

U

U

U

L

L

L

Table 2. Quality assessment of the included studies.

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Primary Analysis

Analysis was performed independently for two categories with follow-up duration either less than 3 years, or 3 years or more. In the category of 29 trials with follow-up less than 3 years, a total of 1,175 (13.3%) participants randomized to the vitamin D group and 1,118 (12.2%) participants randomized to the placebo or no intervention group died. Analysis showed that vitamin D did not significantly decrease all-cause mortality. The risk ratio of mortality for patients treated with vitamin D compared with that of control was 1.04 (95% CI: 0.97–1.12), which was statistically insignificant (P = 0.28), with insignificant heterogeneity (I2 = 12%) (Figure 2A).

In the second category of 13 trials with follow-up of 3 years or longer, a total of 3,693 (10.9%) participants randomized to the vitamin D group and 3,880 (11.5%) participants randomized to the placebo or no intervention group died. Data analysis showed that vitamin D significantly decreased all-cause mortality with a risk ratio of mortality 0.94 (95% CI: 0.90–0.98), which was statistically significant (P = 0.001), with insignificant heterogeneity (I2 = 0%) (Figure 2B).

Sensitivity analysis

Sensitivity analysis was conducted by excluding the trials that had a high risk of bias, the results remain robust. For studies under 3 years (16 RCTs), the risk ratio of mortality for patients treated with vitamin D compared with control was 1.03 (95% CI: 0.86–1.24), which was not statistically significant (P = 0.72), with insignificant heterogeneity (I2 =0%) (Figure 3A). For studies over 3 years (10 RCTs), the risk ratio was 0.94 (95% CI: 0.90–0.98), which was statistically significant (P = 0.008), with insignificant heterogeneity (I2 =0%) (Figure 3B).

Subgroup analysis of long-term follow-up studies

In subgroup analysis (Table 3), significantly decreased mortality was seen in women (RR= 0.91; 95% CI: 0.83–1.00). Data on men were limited with only one related trial. Fewer death were found in patients younger than 80 years (RR= 0.93; 95% CI: 0.88–0.97), but not statistically significant in patients aged 80 years or older (RR= 0.97; 95% CI: 0.90–1.04). A dose of 800 IU or less (RR= 0.93; 95% CI: 0.89–0.98) was found to be more favorable than a dose greater than 800 IU (RR= 0.95; 95% CI: 0.89–1.03). Patients with baseline of 25-hydroxyvitamin D level less than 50 nmol/l treated with vitamin D resulted in significant reduction of mortality (RR= 0.93; 95% CI: 0.89–0.98), whereas no effect was seen in patients with baseline of 25-hydroxyvitamin D leve higher than 50 nmol/l (RR= 0.96; 95% CI: 0.89–1.03). Treatment with cholecalciferol (RR= 0.93; 95% CI: 0.89–0.97) was more favorable than with ergocalciferol (RR= 0.98; 95% CI: 0.90–1.06). Vitamin D combined with calcium was effective to reduce mortality when compared to placebo (RR= 0.94; 95% CI: 0.88–0.99), but not significantly effective when compared to calcium (risk ratio 0.97, 95% CI 0.91 to 1.03). The effect of vitamin D alone treatment was statistically insignificant compared to placebo (RR= 0.93; 95% CI: 0.86–1.00). Vitamin D treatment significantly reduced the cancer mortality (RR= 0.88; 95% CI: 0.79–0.98), but did not decrease cardiovascular mortality (RR= 0.91; 95% CI: 0.81–1.02).

Subgroup

No. of participants

No. of death

Risk ratio (95% CI)

P Value

I2, %

Vitamin D group

Control group

Vitamin D group

Control group

Gender

Male only

1019

1018

199

220

0.88 (0.73–1.07)

0.19

0

Female only

22111

22401

831

919

0.91 (0.83–1.00)

0.04

0

Age

<80 yr

30736

30710

2698

2859

0.93 (0.88–0.97)

0.002

0

≥80 yr

3016

3002

995

1021

0.97 (0.90–1.04)

0.39

0

Dose of oral vitamin D, IU

P=0.61

≤800

29066

28715

2712

2851

0.93 (0.89–0.98)

0.003

0

>800

4686

4997

981

1029

0.95 (0.89–1.03)

0.20

19

Baseline 25-hydroxyvitamin D*

<50

27177

26788

2695

2835

0.93 (0.89–0.98)

0.003

0

≥50

6459

6808

998

1044

0.96 (0.89–1.03)

0.23

0

Type of vitamin D

Ergocalciferol

2210

2529

717

735

0.98 (0.90–1.06)

0.59

45

Cholecalciferol

31542

31183

2976

3145

0.93 (0.89–0.97)

0.001

0

Calcium coadministration status

Vitamin D + calcium vs. calcium

3174

3170

1129

1164

0.97 (0.91–1.03)

0.32

0

Vitamin D + calcium vs. placebo

26367

26054

2008

2098

0.94 (0.88–0.99)

0.02

0

Vitamin D vs. placebo

5110

5087

967

1034

0.93 (0.86–1.00)

0.06

0

Specific mortality

Cancer mortality

22170

22090

558

632

0.88 (0.79–0.98)

0.03

0

Cardiovascular mortality

22170

22090

489

537

0.91 (0.81–1.02)

0.11

0

Table 3. Subgroup benefits at the longer duration of Vitamin D, as compared with control group (Trial level data).

*Based on the reported mean baseline level, irrespective of type of vitamin D assay, in a sample of study participants

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Publication bias

No evidence of publication bias was detected for the risk ratio of mortality in this study by either Begg or Egger’s test. For studies under 3 years, Begg’s test P= 0.837, Egger’s test P= 0.623; For studies over 3 years, Begg’s test P= 0.059, Egger’s test P= 0.055.

Discussion

We conducted a systematic review and meta-analysis to evaluate the best available research evidence regarding vitamin D supplementation on overall mortality. A total of 42 RCTs were included in the present study, quality assessment suggested that the overall study quality was fair and no significant publication bias was detected. Our results demonstrates that vitamin D supplementation longer than 3 years leads to a significant reduction on overall mortality. When trials with a high risk of bias excluded in the sensitive analysis, the results remain robust. The effect of vitamin D on mortality reduction was significant in several subgroups of individuals: female patients, participants with a mean age younger than 80, dose of 800 IU or less, participants with vitamin D insufficiency (baseline 25-hydroxyvitamin D level less than 50 nmol/L) and cholecalciferol therapy. In addition, compared with placebo, vitamin D in combination with calcium significantly reduced mortality.

Our findings confirmed those in an earlier Cochrane systematic review [15] on the effect of vitamin D treatment on overall mortality, which showed that participants with vitamin D insufficiency (25-hydroxyvitamin D level less than 20 ng/ml) decreased the overall mortality significantly, and indicated that cholecalciferol therapy was more favorable than ergocalciferol and that vitamin D as daily doses of 800 IU or less was more favorable than daily doses more than 800 IU. In contrast with two meta-analysis [13,16], which compared daily dose of 800 IU or greater with that less than 800 IU and suggested that daily dose of vitamin D did not differ in the effect on the outcome, our analysis indicated that the beneficial effect of vitamin D is clearly observed in the low daily dose. One explanation may be that several included trials [23,27,30] used intermittent and high dose of vitamin D, which has been suggested less likely to have a benefit, or to even have a negative effect among the elderly [23]. Consumption of intermittent and high dose of vitamin D leads to high concentrations of plasma 25-hydroxyvitamin D. Michaëlsson et al [63] concluded that both high and low concentrations of plasma 25-hydroxyvitamin D were associated with elevated risks of overall and cancer mortality.

A previous meta-analysis conducted by Autier et al [13] suggested that no relationship was found with duration of vitamin D supplement. In contrast, our results indicated that vitamin D supplementation significantly reduced the overall mortality when duration was longer than 3 years compared with that of control. However, no benefit was seen in those with durations less than 3 years. Additionally, two meta-analyses of RCTs with vitamin D treatment on falls also reported that patients benefit from vitamin D supplementation in a longer time duration [64,65].

Our results indicated that vitamin D was effective in reducing mortality among female patients. There was a lack of evidence to draw a conclusion of vitamin D’s influence on male patients with only one identified trial collected death data by subgroup of gender. We concluded that vitamin D may decrease mortality in patients younger than 80 years old, but not in patients aged 80 years or older. However, no statistically significant difference was found for risk ratio of overall mortality between the two age groups (P= 0.59). This results support an early meta-analysis of vitamin D treatment on falls, which indicated that participants with a mean age younger than 80 benefited from vitamin D supplementation [64].

Several previous meta-analyses suggested that vitamin D supplementation reduced all-cause mortality when given together with calcium, but did not support an effect of vitamin D alone treatment [14-16]. In contrast, our results suggested that vitamin D combined with calcium reduced all-cause mortality significantly when compared with placebo (RR= 0.94; 95% CI: 0.88–0.99), but the effect was insignificantly when compared with calcium therapy (RR= 0.97; 95% CI: 0.91–1.03). Vitamin D alone had a trend to decrease mortality (RR= 0.93; 95% CI: 0.86–1.00) when administrated in a long time. It may indicate that calcium therapy does not increase risk of death [66]. Whether vitamin D given together with calcium is more beneficial than calcium alone treatment needs more RCTs to be clarified.

There is not sufficient evidence to draw conclusions of the effect of vitamin D on specific mortality with only 3 trials collected mortality data in a rigorous fashion. Vitamin D may have a beneficial effect on cancer related mortality. But it needs more RCTs to better understand the effect of vitamin D on cancer. Meta-analyses of cohort studies have suggested that vitamin D intake was associated with reduced risk of colorectal cancer [67], breast cancer [68] but not prostate cancer [69]. Vitamin D had no significant effect on cardiovascular disease mortality. A growing number of literature suggest that low levels of vitamin D are associated with cardiovascular disease risk [70-74]. A limited number of interventional studies that investigated the effects of vitamin D supplementation on cardiovascular disease risk showed mixed results [75-78]. The effect of vitamin D on cardiovascular diseases remains to be identified.

The mechanism of vitamin D benefit on overall mortality is not clear. Both forms of vitamin D (D2 and D3) are converted to 25-hydroxyvitamin [25(OH)D] in the liver, and then hydroxylated to 1,25-dihydroxyvitamin D in the kidney [79]. 1,25(OH)2D is the only biologically active form of vitamin D, which increases calcium absorption and bone formation to maintain bone health, regulate blood pressure and insulin production, prevent heart disease, regulate immune function to prevent diabetes and autoimmune disease, regulate cell growth to prevent cancer [80,81].

Vitamin D insufficiency (< 50 nmol/L) has now been linked to a broad spectrum of human diseases from cancer to cardiovascular to autoimmune conditions [82]. Though vitamin D can acquire through cutaneous synthesis after sunlight exposure and nutrition [83], it is often not sufficient to reach the required levels of vitamin D, especially in patients with osteoporosis and fracture risk [84]. In that case, supplementation of vitamin D is required, in order to prevent vitamin D insufficiency and associated adverse outcomes.

Similar to other meta-analyses, our review has several limitations. First, though extensive searches were made, there were no data of Hispanic or Orientals. Second, most of the participants in the present study were older women, the effects of vitamin D on mortality in younger, healthy persons and in males are still inconclusive. Third, the overall RR (95% CI) effect was modest and could be the result of chance alone. Fourth, there were only 13 trials that have durations of follow up longer than 3 years.

In conclusion, our results implicated that long-term supplementation of vitamin D may have a beneficial effect on overall mortality, especially in patients with vitamin D insufficiency and younger than 80 years. Vitamin D in a dose of 800 IU daily or less was found to be more favorable than a dose greater than 800 IU and treatment with cholecalciferol was more favorable than ergocalciferol. Future studies are needed to test the efficacy of vitamin D on specific mortality, such as cancer and cardiovascular disease mortality in a long-term treatment duration.